Secondary Prevention in Metastatic Colorectal Cancer: Benefits of Vitamin D and Aspirin Explored

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Vitamin D Levels and Aspirin Use in Colorectal Cancer

Two low-cost, low-tech options may lead to a survival benefit in metastatic colorectal cancer, according to separate retrospective studies selected for the Best of ASCO® 2015. The first study suggested that vitamin D supplementation is worthy of investigation in this regard,1 and the second study added to existing evidence that regular use of aspirin may improve survival in colorectal cancer.2

“Various standard therapies can improve survival in metastatic colorectal cancer. What else can you do to improve survival in this disease? The take-home message from these studies is that vitamin D levels and aspirin are lifestyle factors most consistently associated with improved outcomes among patients with colorectal cancer. There is strong supportive evidence for both of these interventions, and if confirmed, these low-cost options could have a substantial impact for the treatment of colorectal cancer,” said Daniel G. Haller, MD, of Abramson Cancer Center, University of Pennsylvania, Philadelphia, discussant of these two studies at the Best of ASCO® 2015.

Vitamin D Levels

Higher plasma concentrations of plasma 25-hydroxyvitamin D [25(OH)D, vitamin D] are associated with significantly improved survival in patients with metastatic colorectal cancer treated with chemotherapy and biologics, according to a prospective pretherapy assessment of patients enrolled in CALGB/SWOG 80404, a randomized phase III trial of chemotherapy plus bevacizumab (Avastin), cetuximab ­(Erbitux), or both, prior to the KRAS-wild type amendment for this study.

The study included 2,334 patients randomized as follows: chemotherapy plus bevacizumab (n = 899 patients), cetuximab (902 patients), or both (533 patients). Plasma vitamin D was measured prior to receiving chemotherapy in 1,043 patients. The primary study results showed no significant difference in overall survival among the arms.

Significantly lower plasma vitamin D levels were found in male and black patients; those living in the northeast; and those with lower dietary and supplemental vitamin D intake, an Eastern Cooperative Oncology Group performance status of 1 (vs 0), tumoral RAS mutation, higher body mass index, lower levels of physical activity, and a blood draw during the winter and spring.

Patients in the highest quintile had significantly improved overall survival compared with those in the two lowest quintiles, after adjusting for pathologic and clinical prognostic factors: median of 32.6 months vs 24.5 months (P trend = .001).

Improved progression-free survival was also significantly associated with higher plasma concentrations of vitamin D: median of 12.2 months vs 10.1 months, respectively (P trend = .01). Results were consistent across subgroups.

“These results showed a 35% improvement in overall survival and a 21% improvement in median progression-free survival in the highest quintile compared to the lowest. According to a Forest plot, every subgroup did better with higher levels vs lower levels,” Dr. Haller noted.

Strengths of the study are that vitamin D levels were measured after diagnosis but before treatment and that there is detailed information on other prognostic factors. Patients received protocol-based therapy, and follow-up was standard.

“Limitations [of the study] include lack of data on vitamin D level before the cancer diagnosis. It is also not clear if a single measure of a single form of vitamin D is the best measure,” Dr. Haller continued.

 “There is a preponderance of evidence from several countries that patients with higher vitamin D levels have improved outcomes. This is strong, consistent evidence. It is not clear, however, whether correcting vitamin D levels will lead to improved outcomes,” he noted.

Remaining questions are whether vitamin D supplementation should be given in adjuvant settings, whether vitamin D supplementation improves outcomes only in vitamin D–deficient patients, and what are the best formulations of vitamin D supplements. Two randomized trials are looking at these questions.

“If these findings are confirmed, vitamin D supplementation will represent a low-cost option to further improve metastatic colorectal cancer outcomes,” he stated.

Aspirin Use

Aspirin has been validated in primary prevention of colorectal cancer. A population-based, retrospective, cohort study conducted in Norway between 2004 and 2011 in an unselected cohort of 25,644 patients with colorectal cancer found that aspirin as secondary prevention was associated with improved survival. Twenty-five percent of patients (n = 6,109) were exposed to aspirin, as defined by a prescription of aspirin for more than 6 months after diagnosis of colorectal cancer.

At a median follow-up of 2.2 years, overall survival and colorectal cancer–specific survival were significantly improved in patients who took aspirin. Among those exposed to aspirin, 2,088 (34.2%) deaths were recorded, of which 1,172 (19.2%) were attributed to colorectal cancer. Among nonexposed patients, 7,595 deaths (38.9%) were recorded, of which 6,356 (33.5%) were colorectal cancer–specific. An adjusted multivariate analysis found that aspirin exposure after diagnosis of colorectal cancer was an independent risk factor associated with improved colorectal cancer–specific and overall survival (P < .001 for both ­comparisons).

Dr. Haller cited the following strengths of this study: a large population, unselected patients, high-quality validated data, complete follow-up data, no recall bias, and no lead-time bias. Study limitations are that the dose and duration of aspirin treatment are not known, and there are no data on toxicities.

Remaining questions on the use of aspirin are its optimal dose and duration and identification of molecular markers for which patients will benefit.

“The majority of studies show a positive effect on colorectal cancer–specific survival and overall survival. I think the answer to whether aspirin should be used is a resounding yes,” he said.

Results of two ongoing trials are awaited: CLEAR (Alliance 80702 trial) in stage III colorectal cancer, which has a 2 × 2 factorial design: 3 vs 6 months of adjuvant FOLFOX (leucovorin, fluorouracil, and oxaliplatin) with or without celecoxib for 3 years; and the British Add-Aspirin trial, a randomized, double-blind, placebo-controlled trial after survival in nonmetastatic colorectal cancer. ■

Disclosure: Dr. Haller reported no potential conflicts of interest.


1. Ng K, Venook AP, Sato K, et al: Vitamin D status and survival of metastatic colorectal cancer patients: Results from CALGB/SWOG 80405 (Alliance). 2015 ASCO Annual Meeting. Abstract 3503. Presented May 29, 2015.

2. Bains S, Mahic M, Cvancarova M, et al: Impact of aspirin as secondary prevention in an unselected cohort of 25,644 patients with colorectal cancer: A population-based study. 2015 ASCO Annual Meeting. Abstract 3504. Presented May 29, 2015.